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Abstract Phenotypic expression is often constrained by functional conflicts between traits, and the resulting trade-offs impose limits on phenotypic and taxonomic diversity. However, the underlying mechanisms that maintain trade-offs or allow organisms to resolve them via phenotypic plasticity are often challenging to detect. The trade-off between gas exchange and water loss across respiratory surfaces represents a fundamental trade-off that constrains phenotypic diversity in terrestrial life. Here, we investigate plastic mechanisms that mitigate this trade-off in lungless salamanders that breathe exclusively across their skin. Our field and laboratory experiments identified plastic responses to environmental variation in water loss and oxygen uptake, and gene expression analyses identified putative pathways that regulate this trade-off. Although the trade-off was generally strong, its strength covaried with environmental conditions. At the molecular level, antagonistic pleiotropy in multiple biological pathways (e.g., vasoconstriction and upregulation of aerobic respiration) putatively produce the trade-off, while other pathways mitigate the trade-off by affecting a single trait (e.g., oxygen binding affinity, melanin synthesis). However, organisms are likely to encounter novel trade-offs in the process of bypassing another. Our study provides evidence that alternative pathways allow organisms to mitigate pleiotropic conflicts, which ultimately may allow greater phenotypic diversity and persistence in novel environments.